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Review
. 2025 Jun 10;3(1):25.
doi: 10.1038/s44324-025-00063-4.

ECM formation and degradation during fibrosis, repair, and regeneration

Alejandro E Mayorca-Guiliani  1 , Diana Julie Leeming  2 , Kim Henriksen  2 , Joachim Høg Mortensen  2 , Signe Holm Nielsen  2 , Quentin M Anstee  3   4 , Arun J Sanyal  5 , Morten A Karsdal  2 , Detlef Schuppan  6   7
Affiliations
Review

ECM formation and degradation during fibrosis, repair, and regeneration

Alejandro E Mayorca-Guiliani et al. NPJ Metab Health Dis. .

Abstract

Imperfect attempts at organ repair after repeated injury result in aberrant formation of extracellular matrix (ECM) and loss of tissue structure. This abnormal ECM goes from being a consequence of cellular dysregulation to become the backbone of a persistently fibrotic cell niche that compromises organic function and ultimately drives systemic disease. Here, we review our current understanding of the structure of the ECM, the mechanisms behind organ-specific fibrosis, resolution, healing and regeneration, as well as the development of anti-fibrotic strategies. We also discuss the design of biomarkers to investigate fibrosis pathophysiology, track fibrosis progression, systemic damage, and fibrosis resolution.

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Conflict of interest statement

Competing interests: A.E.M.-G., D.J.L., K.H., J.H.M., and M.A.K. are employees of Nordic Bioscience A/S. D.J.L., K.H., J.H.M., S.H.N., and M.A.K. are Nordic Bioscience A/S stockholders. A.J.S.: has stock options in Durect, Inversago, Tiziana, Rivus, Exhalenz, Genfit. He has served as a consultant to Intercept, Gilead, Takeda, Meck, Eli Lilly, Novo Nordisk, Astra Zeneca, Boehringer Ingelheim, Alnylam, Regeneron, Histoindex, Path AI, Pfizer, 89Bio, Altimmune, Northsea, Akero, Madrigal, Salix, Myovant, Poxel, Surrozen, Hanmi, Aligos, Promed, Zydus. His institution has received grants from Intercept, Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Echosens, Hanmi, Madrigal, Gilead, Salix, Meck, Takeda. He receives royalties from Elsevier and Wolter Kluwers. D.S.: is CMO, co-CEO/CSO for ImmuneNTech, and consults for Falk Pharma, Takeda, Boehringer-Ingelheim, Resalis, Immunic, Sanofi, Northsea Bioscirences.

Figures

Fig. 1
Fig. 1. A schematic of ECM structure.
Although ECM is organ specific, there are characteristics that are common to most tissues, like the presence of a basement membrane and an interstitial matrix. Equally, disease may induce sui generis remodeling, abnormal formation and degradation are shared by several conditions (e.g., IPF, MASLD, COPD, etc.).
Fig. 2
Fig. 2. The balance between ECM formation and degradation.
Homeostatic balance can be broken by repeated injury (infection, environmental exposure, physical or chemical insult, mutations, etc.) and subsequent, insufficient, dysregulated reparative response. How this balance tilts towards determines a distinct functional disruption (endotype). Dynamic biomarkers should identify these endotypes and the activities driving disease as well as a potential regeneration.
Fig. 3
Fig. 3. Local ECM-associated disease drives systemic dysfunction, but new therapies can revert the course.
Schematic highlighting the state-of-the-art of organ regeneration technology (left), and the “Organ death races” that are triggered by local, ECM-associated disease, emphasizing liver and adipose tissue as sources of syndrome-like and ultimately lethal events (right).
Fig. 4
Fig. 4. Outcomes in adults with MASLD.
According to Sanyal AJ et al., patients with chronic steatohepatitis are at higher risk of cardiovascular and renal adverse events than liver-related events. This schematic illustrates the organ death race driven by MASLD progression. (Line thickness represent probability of event per 100 patients).
See this image and copyright information in PMC

References

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